BCG and Kawasaki disease in Mexico and Japan

ABSTRACT

Dr. Tomisaku Kawasaki was the first to describe BCG reactivation in Kawasaki Disease (K_D), and this sign is present in about 30–50% of K_D patients. It is a very specific early sign of the disease and although it has been recognized for decades, its pathophysiology continues to be an enigma. Recently, Yamada et al. reported a severe BCG reaction with tuberculid in 2 Japanese K_D patients. We present 2 cases with K_D and severe BCG reaction, one from Japan and the other from Mexico and review the policies of administration of BCG in both countries. The BCG vaccine has a worldwide coverage of 88%. Differences in BCG strains and methods of administration may influence BCG reactions in K_D. The BCG reaction in the inoculation site may represent the most useful sign in K_D.

KEYWORDS:

• BCG
• Kawasaki disease
• Tuberculid
• tokyo172

We read with great interest the article by Yamada et al. reporting 2 Japanese infants with tuberculid associated with Kawasaki disease (K_D).¹ Reactivation in BCG site is present in about 30–50% of K_D patients.^2-5 The local inflammatory reactivation of the BCG vaccination site was first highlighted in the Japanese literature as a specific early sign of K_D, although it has been recognized for decades, its pathophysiology continues to be an enigma.²

We recently treated 2 K_D patients with unique severe BCG inoculation site reactions. The first, a 6-month-old Mexican girl, fully immunized (BCG administration since birth), with a history of 5 d with fever and maculopapular rash in the face and one day later it generalized to the trunk and extremities. On physical examination she presented with BCG scar erythema and an important ulceration with crust formation in the central zone, erythematous papules in the cheek, conjunctival erythema, erythematous cracked lips and palmar erythema. The papules in the face resembled the tuberculid described by Yamada et al. (Fig. 1). Biopsies in the BCG inoculation site showed important infiltration of the dermis by lymphocytes, eosinophils and multinucleated giant cells. No microorganisms were found. IVIG and aspirin led to complete resolution including the lesions located in the face.

Figure 1. Mexican girl with erythematous papules (tuberculid) in the cheek and erythematous lesion in the BCG inoculation site that ulcerated 2 days later.

The second case is a 5 month-old Japanese child with a history of BCG administration at 3 months of age (In Japan, BCG is administered intradermally with the multipuncture method, i.e. liquid BCG was coated on his upper limb and pierced by a stamp with 9 needles). He presented with a history of fever, rash in the lower legs and back, erythema on the lips and conjunctivitis. On physical examination a severe inflammation in the BCG site with crust formation was noted (Fig. 2). IVIG led to resolution of the fever in 24 hrs. Echocardiogram was normal.

Figure 2. Important erythematous plaque in the BCG inoculation site with crust formation.

The BCG reaction in K_D has been hypothetically attributed to cross-reactivity between mycobacterial heat shock protein (HSP) 65 and a human homolog HSP 63.⁶ BCG immunization has been used in animal models of K_D.^7,8 Nakamura et al. found that coronary arteritis develops from the combination of a primary immunization with BCG and a secondary iummunization with a ubiquitous microorganism.⁷ They hypothesized that a microorganism that shares a cross-reactive antigen with BCG might induce an immunopathologic reaction to both BCG and vascular antigens.⁷ A homolog of peroxiredoxin-2 is conserved in many microorganisms, and this homolog is also expressed in BCG.^7,9,10 Karasawa et al. reported that autoantibodies to peroxiredoxin-2 are found in patients with vasculitis.⁹ Fujieda et al. have found autoantibodies to peroxiredoxin-2 in 43% of K_D patients and its presence correlate with a more severe disease.¹⁰

Of interest is that the reduction in mortality in BCG-vaccinated infants observed in high mortality settings has been atributed to the heterologous (non-specific) effects of BCG on host immunity.^11,12 There are several studies in which macrophage activation or non-specific activation of the reticuloendothelial system is the most likely mechanism by which BCG protect against heterologous infection, including bacteria, parasites, fungi and virus.¹³ K_D has been associated with a variety of different microorganisms that may act as triggers, from viruses to bacteria, parasites and fungus. On the same token BCG reaction in K_D could be partially explained by this atribute of the vaccine.

Tuberculids arise from an immunological reaction triggered by a Mycobacterium tuberculosis infection elsewhere in the body.¹ There are 3 main clinical manifestations of cutaneous tuberculid: lichen scrofulosorum, papulonecrotic tuberculid and erythema induratum of Bazin. There is evidence that it could be an immunological reaction in the skin to haematogenous spread of bacilli or fragments of bacilli. The lesions seen in our patient´s cheeks were clinically compatible with papulonecrotic tuberculid but biopsy was not performed. Tuberculids and the BCG reaction could be linked to the immune activation to an unknown microorganism as suggested by Yamada et al.¹ Another interesting clinical observation is that erythema in both BCG and PPD inoculation sites have been described in K_D, reinforcing the notion that this is a non specific inflammatory reaction.¹⁴ Importantly, it has been suggested that the tuberculin skin test (PPD) could provide a diagnostic tool to identify incomplete forms of KD in non-vaccinated patients.¹⁵ Histopathologic features in the site of BCG vaccine inoculation in K_D have shown inflammatory changes with a predominant CD4+ T lymphocyte and CD13+ macrophage infiltration with detection of interleukin-1 α and tumor necrosis factor α in the lesion.¹⁶ Kuniyuki report a severe reaction with necrotic ulceration in the BCG vaccination site in a K_D patient and the histologic study showed a granulomatous reaction similar to our first case.¹⁷

In 1908, Albert Calmette and Camille Guérin started working with a virulent strain of Mycobacterium bovis that had been isolated from a cow with tuberculous mastitis. In 1921 a newborn in Paris received for the first time this vaccine. The mass vaccination of children was begun and adopted by many countries.

The BCG strain was brought to Japan by Kiyoshi Shiga in 1924. In 1961, the 172nd passage of BCG from the first culture was freezed-dried (the Japanese BCG strain, Tokyo-172).¹⁸ Since 2013, the Japanese government recommends vaccination between 5 months and 11 months of life. BCG vaccine was introduced to Mexico by Fernando Ocaranza, director of the Hygiene National Institute from the Danish strain (1331) from Staten serum Institut Copenhague and is part of the immunization schedule since birth. In Japan, local side effects led the way to find an improved vaccination method. Since 1967, the multiple puncture vaccination method replaced intradermal injections with less local lesions.¹⁸ The BCG in Japan is administered intradermally with the multipuncture method in contrast to Mexico and other countries where only one site of intradermally puncture is used, thus a different morphology of the scar is seen in the BCG inoculation site.¹⁸

BCG strain influences scar prevalence and scar size. BCG strain and route also confer different levels of immune activation. Percutaneous Japanese BCG induce higher frequencies of BCG-specific interferon-γ producing CD4+ and CD8+ T cells in BCG-stimulated whole blood than did intradermal Danish BCG.¹⁹ BCG strain may lead to differences in BCG reactions among K_D patients. Tokyo-172 BCG is currently used in Japan, Taiwan and South Korea, the 3 countries with the highest incidence of K_D.²⁰ Of 15,524 japanese K_D patients (Tokyo-172 strain), 7745 (49.9%) had redness or crust formation at the BCG inoculation site.² Strikingly, 70% of complete K_D patients 3–20 months old presented this finding.² This is in frank contrast to data from mainland China, where 1.7% (10/577) and 0.86% (2/231) BCG erythema among K_D patients have been reported.^21,22 BCG China strain and BCG Pasteur strain are used in mainland China.²³ Ulloa-Guterrez et al. reported 19% (59/311) BCG scar changes in K_D in Latin America where a variety of strains are used.²⁴ A genetic factor could play a role since C-allele of ITPKC SNP have been associated with K_D susceptibility and BCG scar reactivation in Taiwan.²⁵

BCG reaction is an early and specific clinical sign and although not included in the classical diagnosis criteria, provide strong support for the diagnosis. Since 1970, BCG reaction in the inoculation site in K_D was described by Dr. Tomisaku Kawasaki, and to this day continue to be a perplexing phenomenon, nevertheless may represent the most useful sign in the disease.²⁶

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgment

We thank deeply Dr. Alberto Unzueta for reviewing the manuscript and helpful discussions.